Chitosan-hyaluronic acid engineered polycaprolactone nanoparticles enhance curcumin antiplasmodial activity and preserve blood-brain barrier integrity.

Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection associated with endothelial activation, neuroinflammation, and disruption of the blood-brain barrier (BBB). While curcumin (Cur) possesses antiplasmodial and anti-inflammatory properties, its therapeutic potential is limited by poor aqueous solubility, rapid metabolism, and insufficient brain bioavailability. In this study, we hypothesized that polysaccharide-driven surface engineering could regulate nanoparticles (NPs) interfacial properties to improve BBB compatibility and antiplasmodial efficacy. Cur-loaded polycaprolactone (PCL) NPs were fabricated through a single-emulsion solvent evaporation technique and sequentially coated with chitosan (CS) and hyaluronic acid (HA) to establish defined structure-property relationships. The resulting nanoformulations were characterized for particle size, surface charge, polysaccharide deposition, encapsulation efficiency (EE), and release kinetics. In-vitro biological performance was evaluated through hemocompatibility, brain endothelial cell viability, BBB integrity through transendothelial electrical resistance measurements, and in-vitro antiplasmodial activity against P. falciparum FCR3. Dual polysaccharide coating produced stable NPs with controlled size, enhanced surface charge, sustained Cur release, and significantly improved endothelial compatibility compared with free Cur and non-hyaluronic-acid formulations. Notably, HA coating strengthened BBB integrity and enhanced antiplasmodial potency. These findings demonstrate that CS- HA surface functionalization governs critical structure-property relationships, highlighting the potential of polysaccharide-engineered nanocarriers for adjunctive CM drug delivery.